CURRENT ISSUE • JANUARY 2012 • VOL. 60                          SPECIAL ISSUE : COMMUNITY ACQUIRED PNEUMONIA

Point of View

The Cage in Search of a Bird

Sanjay Kalra*

*Executive Editor, Indian J Endocrinology and Metabolism; Editor-in-chief, Intl J Clinical Cases and Investigations; Bharti Hospital and B.R.I.D.E., Karnal 132001, India

The last few years have seen a sudden spurt in interest in malignancy related to diabetes and diabetes related medications.

When modern diabetology began about a century ago, the aim of clinicians was just to keep their patients alive for as long as possible. With the discovery and use of insulin, emphasis shifted to avoiding acute complications such as hypoglycemia and symptomatic hyperglycemia. As diabetes care improved, and the understanding of pathophysiology and natural history of the disease deepened, physicians expanded their ambit to include the prevention and management of chronic complications. A gluco-centric approach was supplanted by a more comprehensive attitude towards diabetes, including focus on macrovascular and microvascular complications.

These changes were driven, in part, by a greater realization of the various mechanisms involved in glycemic metabolism. From a simplistic insulin deficiency-based model, diabetes has progressed to a multipronged pathophysiologic model, also known as the Ominous Octet.1 Newer culprits, such as dopamine, ‘the forgotten felon’, are also being added to this list.2

In parallel, newer drug targets were studied and evaluated for their potential in diabetes management. Much of this research has led to the development, and marketing, of novel drugs. The GLPI analogues, DPP-4 inhibitors and newer insulin analogues, all of which are used in diabetes management, were introduced with the past decade. With all these changes, the horizon of diabetes pharmacotherapy changed dramatically. From a bleak, spartan choice limited to sulfonylureas and biguanides, the practicing physicians was suddenly confronted with a virtually unlimited number of combinations and permutations of antidiabetic therapy. The sky line was full of exciting and promising therapeutic options, which physicians, and guidelines, embraced enthusiastically.3,4 The birds had come to roost. But where there are birds, there will be bird hunters.

Diabetes has always been known to be a pro-carcinogenic state. High levels of glucose, insulin and insulin like growth factor 1 have been implicated in the development of various glucose-dependent malignancies. These include cancers of the breast, colon, prostate, uterus and ovary. Various other mechanisms for this have been mentioned in the occasional reviews on the relationship of diabetes and malignancy published earlier.5 Analysis of data by some authors also revealed that use of insulin per se was a factor which promoted malignancy.6 No hype, however, was created, either in scientific journals or in lay media regarding this.

A few years ago, the Pro-Active trial reported beneficial results of pioglitazone on glycemic control as well as cardiovascular safety. Though the study documented higher rates of bladder cancer in subjects treated with pioglitazone (14 cases) as compared to those on placebo (5 cases), this finding was not given much prominence. The observation was over shadowed by the beneficial effects of pioglitazone on glycemia, and by its cardiovascular safety.7 This was in sharp contrast to the hype created over malignancy related to estrogen replacement therapy, which followed publication of the Women’s Health Initiative Trial.8

In 2010, though, papers were published on the relationship of insulin glargine with malignancy. Glargine use was found to be linked with a higher risk of breast cancer in post menopausal women, though the methodology of these papers was widely criticized.9 These publications created worldwide interest in cancer and diabetes. Reviews were published on this topic, and researchers began to look at all anti diabetic and metabolic drugs with what can only termed as a paranoid index of suspicion.

Moreover, at odds with a controversial 2010 meta-analysis by Sipahi et al, the bird hunters had come out in force. Recently, in 2011, data linking pioglitazone with bladder cancer was published.10,11 Though the authors themselves point out the methodological limitations (and flaws) of their work, this report led to a Trans-Atlantic debate on the use of pioglitazone.12 Similar reports on cancer have been published for GLP-I analogues (medullary thyroid carcinoma), dapaglifozin (cancer of bladder and breast), telmisartan, and insulin. The only antidiabetic drug shown to have favorable effects on proliferation is metformin.13 For telmisartan, too, two new Danish-cohort findings (70 clinical trials and almost 3,25,000 patients) published in April 2011 completely refuted the incidence and risk of cancer associated with ARBs.14,15

The cage, i.e. cancer, is in search of a bird, viz, the antidiabetic drugs. This situation is similar to the situation described by the writer Franz Kafka “I am a cage, in search of a bird”. This quote brings to mind a corrupt judge who keeps on trying to find fault with an innocent poor man, until he succeeds.

Is the current controversy on diabetes and cancer an echo of this story?

Is it created by researches and medical writers including in statistical jugglery and manipulation, until a particular statistical method reveals a significant finding? Is it created by vested interests, which target competing drugs, hoping that negative publicity will hit their sales. Is the controversy fuelled by a ‘’tabloid like’’ mentality, rather than pure scientific attitude, on part of medical journal editors? In search of wider readership, higher impact factors, and the elusive capital factor, do journals encourage sensational news, at the cost of less glamorous findings?

Cancer is a serious matter. There is no denying this fact. And if cancer is iatrogenic, it becomes an even more serious matter. But can one stop using all drugs because they have some adverse effect or the other? The traditional methods of management have proved inadequate to handle the burgeoning burden of the diabetes pandemic. This is why we have found the need to develop newer drugs and technology to tackle diabetes.

Leaving the bird hunters unchecked with their cages in search of innocent birds, will thwart efforts at newer and safer drug development. This is something we, rather, our patients can ill afford. Then, what is the solution? We should strengthen ourselves with current data, trends and techniques, to ensure optional utilization of drugs. Methods of suspecting, screening and diagnosing malignancy should be taught to physicians and endocrinologists. Rational choice of specific hypoglycemic drugs and their combinations should be discussed and assessed in continuing medical education symposia, as well as in journals such as JAPI.

Do not cage the bird. Instead, regulate the bird hunters.

References

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7. The official ProActive results website. http://www.proactive-results.com/. Accessed on 29 July 2011.
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